20-(aliphatic hydrocarbonthio) and 20-(substituted aliphatic hydrocarbonthio) pregnane derivatives



United States Patent Ofiice 3,373,844 Patented Mar. 2, 1965 20-(ALHPHATIC HYDROCARBQNTHIQ) AND 20- (SUBSTITUTED ALHPHATEQ HYDRGCARBSN- THIS) PREGNANE DEREVATWES Alexander D. Cross, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed May 24, 1963, gar. No. 282,845

22 (Ilaims. (Q1. 260--397.1l)

This invention relates to novel cyclopentanopolyhydrophenanthrene derivatives and to processes for their preparation.

More particularly, this invention relates to novel 20- (aliphatic hydrocarbonthio)- and 20-(substituted aliphatic hydrocarbonthio) pregnane derivatives represented by the general formulas:

R g o &

In these formulas R represents a saturated or unsaturated, straight or branched chain aliphatic hydrocarhon residue containing from 1 to 7 carbon atoms, inclusive, such as ethylene, i.e., CH -CH propylene, butylene, but-l-enylene, but-l-inylene, Z-methylbutylene, 2,3-dirnethylbutylene, Z-methylbut-Z-enylene, 2,3-dimethylbut-Z-enylene, 2,3dimethylpentylene, 2,3-dimethylpent- 2-enylene, hexarnethylene, and the like; R represents hydrogen or a methyl group, and X, which is substituted .on a primary, secondary or tertiary carbon atom of the group R, represents hydrogen [in this case R and X taken together can represent, for example, a 3'-methylbutyl (isoamyl) or 3-rnethylbut-2-enyl radical], a halogen, e.g., fluorine or chlorine, an N,N-dialkylamino group, preferably an N,N-di-lower)alkylamino group such as N,N-dimethylamino and the like, a hydroxyl group (in this case R and X taken together can represent, for exam- ,ple, a 3'-methyl-3'-hydroxybutyl radical), an acyl group,

a cyano group, or a carboxyl group.

The symbol i at the ZG-position in the above formulas and in those that follow signifies that the hydrogen, aliphatic hydrocarbonthio and substituted aliphatic hydrocarbonbonthio substituents at the ZO-position can be in either the 05- or the fl-configuration.

The acyl and acyloxy groups referred to hereinabove are derived from carboxylic acids, preferably hydrocarbon carboxylic acids, of less than 12 carbon atoms. These acids can be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, or aromatic,

and may be substituted with functional groups such as hydroxyl groups, alkoxy groups containing up to 5 carbon atoms, acyloxy groups containing up to 12 carbon atoms, nitro groups, amino groups and halogens. Typical ester groups are the acetate, trimethylacetate, t-butylacetate, aminoacetate, phenoxyacetate, propionate, B-chloroprcpionate, cyclopentylpropionate, enanthate, and benzoate.

The novel ZO-(aliphatic hydrocarbonthio)- and ZO-(substituted aliphatic hydrocarbonthio) pregnenes represented by Formulas A and B above are progestational agents, and in addition are of great utility in lowering blood cholesterol levels,

The compounds of the present invention can be obtained by the methods illustrated by the following sequence of reactions:

0: VIII VII In the above formulas each of R, R R and X have the same meanings as set forth hereinabove for Formulas A and B, and R represents a saturated or unsaturated, straight or branched chain aliphatic hydrocarbon residue containing one less carbon atom than the group R in the preceding compound (III).

In practicing the methods outlined above, the starting material (1), Le, pregnenolone or 19-nor pregnenolone, is reacted with a monothioglycol of up to 7 carbon atoms, such as fi-mercaptoethanol, v-rnercaptopropanol, l-rnercaptopropanol-Z, a-rnercaptobutanol, and the like, to

yield the corresponding 20-monothioketal (II), e.g., 20 (cycloethylenethiooxy)-pregnenolone, or the corresponding l9-nor compound. This reaction will generally be carried out in the presence of a strong acid, e.g., p-toluenesulfonic acid and the like, preferably in solution in an inert organic solvent such as benzene and the like, at reflux temperature, and will usually take about 12 hours, although longer or shorter reaction times coupled with lower or higher temperatures may be employed if desired.

The 20-monthioketal (II) is then heated with a cleaving agent, as described in my copending US. patent application Serial No. 282,848, filed on May 24, 1963 e.g., a double metal hydride containing at least one element of sub-group IIIA of the Periodic Chart [as set forth at pages 56 and 57 of Langes Handbook of Chemistry, Ninth Edition (Sandusky, Ohio: Handbook Publishers, Inc., 1956)], such as lithium aluminum hydride, potassium aluminum hydride, magnesium aluminum hydride, lithium gallium hydride, zinc aluminum hydride, sodium borohydride, potassium borohydride, aluminum borohydride, and the like, together with a Lewis acid containing no active hydrogen, and preferably a Lewis acid containing an element having an atomic number of 26 to 28 inclusive or an element of subgroup IIIA of the Periodic Chart, such as ferric chloride, boron trifluoride, boron trichloride, aluminum fluoride, aluminum chloride, aluminum bromide, gallium chloride, and the like, to yield the corresponding 20w and ZOfi-(hydroxy aliphatic hydrocarbonthio)-A -pregnenes or their 19-nor derivatives (III), e.g., ZOocand ZOB-(T-hydroxyethyltbio)-A pregnen-3-B-ol being obtained by reacting ZO-(cycloethylenethioxy)-A -pregnen-3,B-ol with lithium aluminum hydride and aluminum chloride in tetrahydrofuran. This reaction will generally be carried out in an organic solvent having an ether function in its molecule, e. g., diethyl ether, tetrahydrofuran and the like, at a temperature ranging from room temperature (about 25 C.) or lower to reflux temperature or above for a period of time ranging anywhere from about 30 minutes to about 24 hours. The 20aand ZOE-derivatives can be separated by conventional chromatographic methods.

These 20(1- and ZOB-(hydroxy aliphatic hydrocarbonthio)-A -pregnenes and 19-nor pregnenes, e.g., 2000- and 20B (2' hydroxyethylthio) A -pregnen-3B-ol, when treated under conventional Oppenauer conditions followed by Jones oxidation (e.g., with 8 N chromic acid), yield the correspondng ZO-(carboxy aliphatic hydrocarbonthio)-A -pregnen-3-ones and their l9-nor derivatives (IV) having one less carbon atom in the group R than the preceding compounds, e.g., 200aand 20,8-(carboxymethylthio -A -pregnen-3 -one.

The 3-keto group in these carboxy derivatives (IV) is then protected by ketalization, e.g., using ethylene glycol in the presence of p-toluenesulfonic acid. Thus, 20aand ZOfi-(carboxymethylthio)-A -pregnene-3-one and the corresponding l9-nor compounds yield 3-(cycloethylenedioxy)-20uand 20,8-(carboxymethylthio)-A -pregnene and the corresponding l9-nor compounds (V).

Reduction of these 3-ketals (V), e.g., with lithium aluminium hydride, afiords the corresponding 3-keta1s of the 200? and 20,8-(hydroxy aliphatic hydrocarbonthio)-A pregnenes and their l9-nor derivatives (VI; X=OH), e.g., 3-(cycloethylenedioxy)-20aand 20B-(2'-hydroxyethylthio -A -pregnene These 3-ketals of the 20w and ZOB-(hydroxy aliphatic hydrocarbonthio)-A -pregnenes and their 19-nor derivatives, when tosylated by known procedures, e.g., using tosyl chloride in pyridine, yield the corresponding 3- ketals of 20-(tosyloxy aliphatic hydrocarbonthio)-A pregnenes and their 19-nor derivatives, e.g., 3-(cycloethylenedioxy) 20aand 2Ofl-(2'-tosyloxyethylthio)-A pregnene.

These tosylated intermediates, when heated at reflux temperature with an alkali metal halide, such as lithium chloride, potassium fluoride, potassium chloride, sodium inert organic solvent such as dioxane and the like, gives the corresponding 3-ketals of the 20-(N,N-dialkylamino aliphatic hydrocarbonthio)-A -pregnenes and their l9-nor derivatives [VI; X=N(alkyl) e.g., 3-(cycloethylenedioxy)-20aand 20,8-[2'(N,N-dimethylamino)-ethylthio]- A -pregnene.

Treatment of the tosyloxy intermediates with an alkali metal cyanide, e.g., sodium cyanide, potassium cyanide, and the like, preferably in solution in an inert organic solvent such as acetonitrile and the like, produces the corresponding S-ketals of the 20-(cyano aliphatic hydrocarbonthio)-A -pregnenes and their l9-nor derivatives (VI; X=CN), e.g., 3-(cycloethylenedioxy)-20aand 20B- 2-cyanoethylthio -A -pregnene.

These 20-(cyano aliphatic hydrocarbonthio) compounds, when subjected to conventional basic hydrolysis, e.g., using sodium hydroxide. or the like, afford the corresponding 3-ketals of the ZO-(carboxy aliphatic hydrocarbonthio)-A -pregnenes and their l9-nor derivatives (VI; X=COOH), e.g., 3-(cycloethylenedioxy)-20aand 20.8- (2'-carboxyethylthio)-A -pregnene being obtained by hydrolyzing the cyano groups in 3-(cycloethylenedioxy)- ZOzxand 201%(2-cyanoethylthio)-A -pregnene.

Treatment of the 20-(carboxy aliphatic hydrocarbonthio) compounds with a lower alkyl magnesium halide,

such as methyl magnesium bromide and the like, under conventional conditions, produces the corresponding 3- ketals of the 20-(n'-hydroxy-n'-alkyl aliphatic hydrocarbonthio)-A -p1'egnenes and their l9-nor derivatives (VI; X=OH), n being the carbon atom of the aliphatic hydrocarbonoxy group to which the hydroxy and alkyl groups are attached, e.g., 3-(cycloethylenedioxy) 20aand 20;8-(3'-hydr0xy 3 methylbutylthio)-A -pregnene being the products resulting from the reaction of 3- (cycloethylenedioxy)-20aand 20B (2' carboxyethylthi0)-A -pregnene with methyl magnesium bromide. Dehydration of these 20-(n-hydroxy-n-alkyl aliphatic hydrocarbonthio) intermediates, for example by treatment with mesyl chloride in dimethylformamide-pyridine at about C. for about 3 hours, results in the corresponding 3-ketals of the 20-(unsaturated aliphatic hydrocarbonthio)-A -pregnenes and their 19-nor derivatives (VI; X=H, R is unsaturated), e.g., 3-(cycloethylenedioxy)- 20:1- and 20,6-(3'-hydroxy 3 methylbutylthio)-A -pregnene yielding, on dehydration, 3-(cycloethylenedioxy)- ZOocand 20,6-(3-methylbut 2' enylthio)-A-pregnene. Catalytic hydrogenation of these 17-(unsaturated alphatic hydrocarbonthio)-A -pregnenes and the corresponding 19- nor compounds, e.g., at atmospheric pressure using a 5% palladium-on-charcoal catalyst, results in the corresponding 3-ketals of the 200w. and ZOfi-(saturated aliphatic hydrocarbonthio)-A -pregnenes and their l9-nor derivatives (VI; X=H, R is saturated), e.g., 3-(cycloethylenedioxy)- 20ocand 20B-(3'-methylbut 2 enylthio)-A -pregnene yield, on catalytic hydrogenation, 3-(cycloethylenedioxy)- 20ocand ZOB-(isoamylthio)-A pregnene.

All of the aforementioned 3-ketal-A pregnene derivatives (VI) can be convert-ed into the corresponding A pregnen-3-ones (VII) by conventional acid hydrolysis,

e.g., using hydrochloric acid.

tetrahydrofuran.

sponding acid chloride, e.g., a mixture of acetic anhydride and acetyl chloride, at reflux temperature, gives the corresponding enol acylates which, upon reduction with an alkali metal borohydride, e.g., sodium borohydride and the like, in an ethanol-tetrahydrofuran solution for about 3 hours at about C. to C., followed by refluxing of the resulting reaction product with a base, such as sodium hydroxide and the like, afford the corresponding 20-(aliphatic hydrocarbonthio) and -(substituted aliphatic hydrocarbonthio)-A -pregnen-3fi-ols and their 19-nor derivatives (VIII; R =H).

The compounds of the present invention having a primary or a secondary hydroxyl group are preferably acylated by reaction with a suitable acid chloride or anhydride in pyridine in the manner well known in the art, while the compounds of the present invention having a tertiary hydroxyl group are preferably esterified by reaction with a suitable acid anhydride in pyridine, in the presence of an acid catalyst such as p-toluenesulfonic acid and the like, again in the manner well known in the art.

The following specific examples serve to illustrate, but are not intended to limit the scope of the present invention.

Example I A mixture of 5 g. of pregnenolone, 150 cc. of anhydrous benzene, 60 cc. of [3-mercaptoethanol and 800 mg. of p-toluenesulfonic acid monohydrate was refluxed for 12 hours with the use of an adapter for the continuous removal of the water formed during the reaction. Aqueous sodium bicarbonate solution was added to the cooled mixture and the organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from acetone-hexane to give 20-cycloethylenethioxy-A -pregnen-3e-ol (Compound No. 1).

Example II A solution of 1 g. of compound No. 1 in 50 cc. of tetrahydrofuran was added over a 30 minutes period to a stirred suspension of 1 g. of lithium aluminum hydride and 5 g. of aluminum trichloride in 50 cc. of anhydrous The mixture was refluxed for 2 hours, then cooled and cautiously treated with 5 cc. of ethyl acetate and 2 cc. of water. Solid sodium sulfate was added, the inorganic material filtered off and thoroughly Washed with hot ethyl acetate, the combined organic solutions upon evaporation yielded a crude material, which after chromatography on alumina and crystallization of the solid fractions from acetone-hexane yielded 20 642- hydroxyethylthio)-A -pregnen-3,8-ol (Cpd. No. 2) and 20w(2' hydroxyethylthio)-A -pregnen-3,8-ol (Cpd. No. 3).

Example III A solution of l g. of compound No. 2 in 80 cc. of toluene and 20 cc. of cyclohexanone was dried by distilling oh. cc. of the solvent. A solution of 1 g. of aluminum isopropoxide dissolved in 7 cc. of anhydrous toluene was then added and the mixture Was refluxed for 45 minutes; 4 cc. of acetic acid were added and the solvents removed by steam distillation. The product was extracted several times with ethyl acetate and the organic extracts washed with 5% hydrochloric acid solution, Water, 10% sodium carbonate solution and water until neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetonehexane afforded 20B-(2'oxoethylthio)-A -pregnen-3-one (Cpd. No. 4).

Example IV A solution of l g. of compound No. 4 in 10 cc. of acetone was cooled to 0 C. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. It was stirred for 5 minutes further at 5 C. and diluted with Water. The precipitate was collected, washed with water and dried under vacuum, thus affording a crude product which upon recrystallization from acetone-hexane gave ZOB-(carboxymethylthio)-A -pregnen-3-one (Cpd. No. 5).

Example V The compound No. 5 was treated according to Example I except that ethyleneglycol was used instead of. B-mercaptoethanol thus yielding I i-cycloethylenedioxy- ZOfi-(carboxymethylthio)-A -pregnene (Cpd. No. 6).

Example VI A solution of 1 g. of compound No. 6 in 50 cc. of tetrahydrofuran Was added over a 30 minute period to a stirred suspension of 1 g. of lithium aluminum hydride in 50 cc. of anhydrous tetrahydrofuran. The mixture was refluxed for 2 hours, then cooled and cautiously treate'd'with 5 cc. of ethyl acetate and 2 cc. of water. Solid sodium sulfate was added, the inorganic material filtered off and thoroughly Washed with hot ethyl acetate, the combined organic solutions upon evaporation yielded a crude material, which was purified by crystallization from acetone-hexane, thus giving 3-cycloethylenedioxy-20f3- (2'-hydr0xyethylthio)-A pregnene (Cpd. No. 7).

Example VII A solution of 1 g. of compound No. 7 in 5 cc. of pyridine was treated with 0.5 g. of tosyl chloride and kept at room temperature for 24 hours; it was then di' luted with Water and the precipitate separated by filtration, thus giving 3-cycloethylenedioxy-20,B-(2-tosyloxy ethylthio)-A -pregnene (Cpd. No. 8).

Example VIII A suspensionof 10 g. of. potassium fluoride in 50 cc. of dimethyl formamide was heated to boiling and'then a solution of 2 g. of compound No.8 in 10 cc. of dimethyl formamide was added. The mixture was refluxed for 5 hours, cooled and poured into water. The formed precipitate was filtered off and crystallized to give 3 cycloethylenedioxy 20,8 (2' fluoroethylthio) A pregnene (Cpd. No.9).

Example IX The compound N0. 8 was treated according to Exam ple VIII, except that potassium chloride was used instead of potassium fluoride, thus yielding 3-cycloethylenedioxy- 3-(2-chloroethylthio)A -pregnene (Cpd. No. 10).

Example X A solution of l g. of compound No. 8 in 50 cc. of dioxane was treated with a constant stream of dimethylamine during 48 hours. Thereafter, the solution was boiled under reflux for minutes and poured into' Water, thus affording a precipitate which was filtered off, dried and recrystallized from methanol-benzene, thus furnishing 3 cycloethylenedioxy 20B .(2 [N,N dimethyl amino]-ethylthio)-A -pregnene (Cpd. No. 11).

Example XI A mixture of 1 g. ofcompound No. 8, 1 g. ofpotas sium cyanide and cc. of acetonitrile was kept at C. for 3 hours. The mixture was then poured into water, and the formed precipitate filtered off, dried and crystallized from acetone-hexane thus yielding 3-cycloethylenedioxy-ZOB-(2'-cyanoethylthio) A pregnene (Cpd. No. 12

Example XII A mixture of l g. of compound No. 12 and 50 cc. of a 5% solution of sodium hydroxide in methanol was re fluxed during 4 hours, then cooled, neutralized with acetic acid and diluted with Water. The formed precipitate overnight.

was collected by filtration and recrystallized from acetonehexane, thus yielding 3-cycloethylenedioxy-20fl-(2'-carboxyethylthio)-A -pregnene (Cpd. No. 13).

. Example XIII a A solution of 5 g. of compound No. 13 in 250 cc. of thiophene-free benzene was treated with 55 cc. of 4 N- methylmagnesium bromide in ether and the mixture refluxed with the exclusion of moisture for 3 hours. The cooled mixture was cautiously treated with excess aqueous ammonium chloride solution and the product isolated by ethyl acetate extraction. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness.

Recrystallization .from methylene chloride-hexane afforded 3 cycloethylenedioxy-ZOB-(3-hydroxy-3-methylbutylthio)-A -pregnene (Cpd. No. 14).

Example XIV 1 g. of compound No. '14 was dissolved with slow heating in 12.5 cc. of dimethyl formamide, the mixture was cooled, 0.42 g. of mesyl chloride and 0.5 cc. of pyridine were added and the solution was kept at 80 C. for half an hour. The reaction mixture was cooled, water was added and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from acetone-hexane furnished 3 cycloethylenedioxy-20fi-(3'-methyl-but-2-enylthio)-A -pregnene (Cpd. No. 15). i

Example XV A suspension of 0.5 g. of 5% palladium on charcoal catalyst in 50 cc. of methanol was hydrogenatedfor 30 minutes. A solution of 2 g. of compound No. 15 in 200 cc. of methanol was added to the catalyst and stirred under a hydrogen atmosphere until one mol equivalent of hydrogen was taken up. After removal of the catalyst by filtration the solution was evaporated and the crude residue was purified by crystallization from methylene chloride-hexane, thus giving 3-cycloethylenedioxy-20fi- (isoamylthio)-A -pregnene (Cpd. No. 16).

Example XVI A solution of 500 mg. of compound No. 7 in 25 cc. of acetone was treated with'0.1 cc. of concentrated hydrochloric acidand the mixture kept at room temperature It wasthen poured into water, extracted with methylene chloride and .the organic extract washed with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetonehexane gave 2018-(2'-hydroxyethylthio)-A -pregnen-3-one (Cpd. N0. 17).

The compounds Nos. 9, 10, 13, 14, and 16 were treated according to the same procedure, thus affording respectively:

Cpd. No.:

18-20fi- (2'-fluroethylthio) -A -pregnen-3 -one, -1920fi- (2'-chl'oroethylthio -A -pregnen-3 -one, 20-2 0,6- (2-carb oxyethylthio -A -pregnen-3-one, 2 120j3- 3 '-hydroxy-3 '-methyl-butylthio -A -pregnen-3-one, v V 2220,8-(3-methyl-but-2-enylthio) -A -pregnen- 3-one, 23 205-(isoamylthio)-A-pregnen-3-one.

Example XVII A solution of. 5 g. of compound No. 24 in a mixture of 100 cc. of 95% ethanol and 35 cc. of tetrahydrofuran was cooled to 10 C. and added dropwise, with occasional stirring over a 1 hour period, to a cold solution of 6 g. of sodium borohydride in 50 cc. of ethanol, the reaction temperature not being allowed to exceed 5C. After completion of addition, the solution was kept at 0-5 C. for 2 hours further; then 200 cc. of 10% sodium hydroxide was added and the solution boiled for 15 minutes. Most of the solvent was removed in vacuo, the residue neutralized with 20% hydrochloric acid and the crystalline precipitate collected and washed. Recrystallization of the crude material from acetone furnished 20p-(2-hydroxy ethylthio)-A -pregnen-3B-ol (Cpd. No. 25).

The compounds Nos. 18 to 23, inclusive, were treated according to the latter procedures, thus atfording as final products:

Cpd. No.:

2720[3- (2'-chloroethylthio -A -pregnen-3 3-01,

28-20,3- (2'-carboxyethylthio -A -pregnen-3fl-ol,

29-205- (3 -hydroxy-3 '-methylbutylthio -A -p re gnen-3B-ol,

3 l20,B- (isoamylthio -A -pregnen-3 18-01.

Example XVIII A solution of 500 mg. of compound No. 11 in 25 cc. of acetone was treated with 0.1 cc. of concentrated hydrochloric acid and the mixture kept at room temperature overnight. It was then poured into water containing 250 mg. of sodium hydroxide extracted with methylene chloride and the organic extract washed with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 2013- (2'- [N,N-dimethylamino] ethylthi'o A pr gnen- .3-one (Cpd. No. 32).

Example XIX The compound No. 32 was treated according to Example XVII, thus furnishing as final product: 20,342- [N,N dimethylamino]-ethyltl1io)-A -pregnen-3fl-ol (Cpd. N0. 33).

Example XX The compound No. 3 was successively treated according to Examples III, IV, V, VI and VII, thus yielding re spectively:

Cpd. No.:

34-20oc- (2'-oxoethylthio) -A pregnen-3-one.

3 520a- (carboxymethylthio -A -pregnen-3 -one.

3 6-3 -'cycloe+thylen.edioxy-20oz- (carboxymethylthio A -pregnene,

3 73 -cycloethylenedioxy-20u (2'-hydroxyethylthio) -A -pregnene,

3 83-cycloethylenedioxy-20 a- 2'-tosyloxyethylthio) -A -pregnene.

Example XXI The compound No. 38 was treated according to Examples VIII, IX, X, and XI, thus yielding respectively:

'Cpd. No.:

39-3-cycloethylenedioxy-20a- (2-fiuoroethylthio) A -pregnene,

403 -cycloethylenedioxy-ZOa- (2'-chloroethylthio A -pregnene,

41--3-cycloethylenedioxy-20a-(2-[N,N-dimethylamino] -ethylthio -A -pregnene,

42-3-cycloethylenedioxy-20a- (2-cyano-ethylthio A -pregnene. I

Example XXII The compound No. 42 was treated successively in ac:

9 cordance with Examples XII, XIII, XIV and XV, thus yielding respectively:

Cpd. No.:

43-3-cycloethylenedioxy-20u- (2-carboxyethylthio) -A -pregnene,

44-3-cycloethylenedioxy-20u-(3-hydroxy-3- methylbutylthio -A -pregnene,

45-3-cycloethylenedioxy-(3-rnethyl-but-2'-enylthio) -A -pregnene,

46-3-cycl0ethylenedioxy-20ot- (isoamylthio) -A pregnene.

Example XXIlII The compounds Nos. 37, 39, 40, 43, 44, 45 and 46 were treated according to Example XVI, thus yielding respectively:

Cpd. No.1

47-20ot- (2'-hydroxyethylthio) -A -pregnen3-one,

48-201 (2'-fiuoroethylthio -A -pregrlen-3-one,

49-2004- (2'-chloroethylthio -A -pregnen-3-one,

5 -20u- (2-carboxyethyllthio -A -pregnen-3-one,

1-20 11- 3 '-hydroxy-3 -methylbutylthio -A -'pregnen-3-one,

5 2-201 3 -rnethyl-but-2-enyl'thio -A -pregnen-3- one,

5 3-20a- (isoamylthio) -A -pregnen-3-one.

Example XXIV The compounds Nos. 47 to 53, inclusive, were treated according to the procedures described in Example XVII, thus affording respectively, as final products:

Cpd. No.:

54-20a- 2-hydroxyethylthio -A -pregnen-3fi-ol, 55-2004- (2'-fiuoroethylthio) -A -pregnen-3,8-o1, 5 6-2011- 2'-chloroethylthio -A -pregnen-3 8-01, 57-20ot- (2'-carboxyethylthio -A -pregnen-3fl-ol, 58200c- (3 '-hydroxy-3 -methylbutylthio) -A -pregnen-3,B-ol,

59-20a- 3 '-methyl-but-2-enylthio) -A -3,8-ol, 60-201m-(isoamylthio)-A -pregnen-3,8-ol.

Example XXV The compound No. 41 was treated successively according to Examples XVIII and XIX, thus yielding respectively 2004 (2- [N,N-dimethylamino] -ethylthio -A -'pregnen-3- one (Cpd. No. 61) and ot-(2'-[N,N-dimethylamino]- ethylthio)-A -pregnen-3,8-ol (Cpd. No. 62).

Example XXVI The known IQnHOI-PI'egHeIIOlOHB (obtained according to US. Pat. No. 3,071,581) was treated according to Example I, thus yielding ZO-cycloethylenedioxy-19-nor- A -pregnen-3 8-ol (Cpd. No. 63), which upon treatment by the procedure of Example II, yielded ZOQ-(Z-hydroxyethylthio)-19-nor-A -pregnen-3B-ol (Cpd. No. 64) and 20w (2'-hydroxyethylthio) -19-n0r-AF-pregnen-3flol (Cpd. N0. 65).

Example XX VIII I 9 Example XX VIII The compound No. 70 was treated according to Examples VIII, IX, X, and XI, thus yielding respectively:

Cpd. No.:

7 1-3 -cycloethylene dioxy-ZOfl- (2'-fiu oroethylthio) -19-nor-A -pregnene,

72-3-cycloethylenedioxy-20,B- 2-chloroethylthio) -19-nor-A -pregnene,

73-3-cycloethylenedioxy-20;8- (2- [N,N-dime-thylamino] ethylthio 1 9-nor-A -pregnene,

74-3-cycloethylenedi0xy-20B- (2'-cyanoethylthio) -19-nor-A -pregnene.

Example XXIX The compound No. 74 was treated successively in accordance with Examples XII, XIII, XIV, and XV, thus yielding respectively:

Cpd. No:

75-3-cycloethylenedioxy-20fl- (2'-carboxyethylthio) -l9-nor-A -pregnene,

76-3-cycloethylenedioxy-20fl-( 3 '-hydroxy-3'- methylbutylthio)-19-nor-A -pregnene,

77-3 -cycl0ethylenedioxy-20/3- 3 rnethyl-but-Z enylthio) l9-nor-A -pregnene,

78-3 -cycloethylenedioxy-20B-( isoarnylthio)- l9-nor-A pregnene.

Example XXX The compounds Nos. 69, 71, 72, 75, 76, 77 and 78 were treated according to Example XVI, thus yielding respectively:

Cpd. No.:

79-20 8-(2'-hydroxyethylthio)-19-nor-A pregnen-3-one,

80-20/3- (2-fluoroethylthio 1 9-nor-A -pregnen- 3-one,

81-206-(2-chloroethy1thio) -'l9-nor-A -pregnen-3-one,

82-20,8- 2-carboxyethyl-thio -19-nor-A -pregnen-3 -one,

83-205 3 -hydroxy-3 '-met-hyl-butylthio) -19- n0r-A -pregnen-3 -one,

84-20,8- (3-rnethy1 but-2-enylthio) -l9-nor-A pregnen-3 -one,

85-205- isoamylthio -19-n0r-A -pregnen-3 -one.

Example X XX I The compounds Nos. 79 to 85, inclusive, were treated according to the procedures described in Example XVII, thus affording respectively, as final products:

Cpd. No.

86-205- 2'-hydroxyethylthio) l 9-nor-A -pregnen-3 3-01,

87-20% 2' fluoroethylthio 1 9"-nor-A -pregnen-3 ,B-ol,

88-20(3- 2'-ehloroethylthio) l9-nor-A -pregnen- 89-20(3-(2-carboxyethylthio)-19 nor-A -pregnen- 90-205- (3 '-hydroxy-3 -rnethylbutylthio) -19- nor-A -pregnen-3 8-01,

91-205-(3 '-rnethylbut-2'-enylthio l9-nor-A pregnen-3 B-ol,

92-205- (isoamylthio) -19-n0r-A -pregnen-3 8-ol.

Example XXXII The compound No. 73 was treated successively according to Examples XVIII and XIX, thus yielding respectively: 20,8-(2'-[N,N-dimethylamino] ethylthio) 19- nor-A -pregnen-3-one (Cpd. No. '93) and,20/3-(2'-[N,N- dimethylamino] ethylthio)-19-nor-A -pregnen-3fi-o1 (Cpd. No. 94).

11 Example XXXIII The compound No. 65 was successively treated according to Examples III, IV, V, VI, and VII, thus yielding respectively: Cpd. No.:

9520 x-(2'-oxoethylthio)-19-n0r-A -pregnen- 3 -one,

9 620a- (carboxymethylthio -19-nor-A -pregnen- 3-one, 973 -cycloethylenedioxy-20u-(carboxymethylthio)-l9-nor-A -pregnene,

9 8--3 -cycloe-thylenedioxy-20a- (2'-hydroxyethylthio -l9-nor-A -pregnene,

' 993 -cycloethylenedioxy-20a- 2-tosyloxyethylthio) -19-nor-A -pregnene.

Example XXXIV The compound No. 99 was treated according to Examples VIII, IX, X, and XI, thus yielding respectively:

Cpd. No.:

1003 -cycloethylenedioxy-20a- (2'-fluoroethylthio) -19-nor-A -pregnene, 101-3-cycloethylenedioxy-20a-(2-chloroethylthio -19-nor-A -pregnene,

1023 -cycloethylenedioxy-20a- (2'- [N,N-dimethylamino] -et-hylthio) -l9-nor-A -pregnene,

l033-cycloethylenedioxy-20ot-(2-cyan0ethylthio)- l9-nor-A -pregnene.

Example XXX V The compound No. 103 was treated successively in accordance with Examples XII, XIII, XIV, and XV, thus yielding respectively:

Cpd. N;:

104-3-cycloethylenedioxy-20a-(2'-carboxyethylthio) l9-nor-A -pregnene, 105-3 -cycloethylenedioxy-20a-(3-l1ydroXy-3'- methy-lbutyl-thio) -19-no-r-A -pregnene, 106--3-cycloethylenedioxy-20e-(3'-'rnethyl-'but-2- enylthio) l9-nor-A -pregnene, 107-3cycloethylenedioxy-20a-isoamyloxy-19- nor-A -pregnene.

Example XXXVI Example XXX VII The compounds Nos. 108 to 114, inclusive, were treated according to the procedures described in Example XVII thus afiording respectively, as final products:

Cpd. No.:

1 15 201 (2'-hydroxyethylthio) 19-n0r-A -pregnen- 3/3-01, 1 16-20u-(2'-fiu0roethylthi0)-19-n0r-A -pregnen- 38-01, 1 17-20m-(2'-chl0roethylthio)-19-nor-A -pregnen- 1-18-201(2-carboxyethylthio) 19-nor-A -pregnen- 1 19-20OL- (3'-hydr0xy-3'-methylbuty1thio -19-nor- A -pregnen-3p-0l,

200c-( 3 -methyl-but-2'-enylthio) -19-nor-A pregnen-3B-ol,

12120a- (isoamylthio) 19-nor-A -pregnen-3 5-01.

Example XXXVIII The compound No. 102 was treated successively according to Examples XVIII and XIX, thus yielding respectively:

20u-(2-[N,N-dimethylamino].ethy1thio)-19-nor-A pregnen-3-one (Cpd. No. 122) and 20oc-(2'-[N,N-dimethylamino]ethylthi0)-19-nor-A pregnen 3e ol (Cpd. N0. 123

Example XXXIX A mixture of 1 g. of 20/i-(2'-hydroxyethy1thio)-A pregnen-3-one (Cpd. No. 17), 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 2015-(2'-acetoxyethylthio)-A pregnen-I-l-one (Cpd. No. 124).

The compounds Nos. 25 to 31, inclusive, 54 to 60, inelusive, 86 to 92, inclusive, and 115 to 121, inclusive, were treated by the above procedure, thus affording respectively:

Cpd. No.:

12520[3- (2-acetoxyethylthio -A -pregnen-3 5-01 acetate,

12720;3-(2-chloroethylthio)-A -pregnen-3fi-ol acetate,

I 12820/3- (2'-carboxyethylthio) -A -pregnen-318-ol acetate,

1292-0,8-(3'-hydroxy-3'-methylbutylthio)-A -pregnen-3,8-0l acetate, 1 3 020,8- 3 '-methyl-but-2-enylthi0) -A -pregnen-3flol acetate, 13 120,B- (isoamylthio) -A -pregnen-3 13-01 acetate, 13220u (2'-acetoxyethylthio) -A -pregnen-3 8-01 acetate, 13 320a (2'-fluoroethylthio) -A -pregnen-3/3-01 acetate,

1 34--20oc-(2'-Ch101OBthylthi0) -A -pregnen-3p-0l acetate, 13 52 Ooc- (2'-carb0xyethylthio -A -pregnen-3 [i-ol acetate, 13 6- -2011- 3 '-hydr0xy-3 '-methylbutylthi0) -A -pregnen-3 8-01 acetate, 13720a- 3'-methyl-but-2'-enylthi0) -A -pregnen-3,B-

01 acetate, 13 820a- (isoamylthio -A -pregnen-3,8-ol acetate, 13 9-20[3- (2'-acetoxyethylthio) 19-nor-A -pregnen- 3 18-01 acetate, 140-205- (2'-flu0r0ethylthi0) l9-nor-A -pregnen-3fiol acetate, 14120fl-(2-chlor0ethylthi0) -19-n0r-A -pregnen- 35-01 acetate, 14220,8- 2'-carboxyethylthio -19-n0r-*A -p'regnen- 3,6-01 acetate, 143-205- 3 '-hydr0xy-3 '-methylbutylthio -19-n0r- A -pregnen-3B-0l acetate, 14420/3- (3 -rnethyl-but-2'-enylthio l9-nor-A pregnen-3,B-ol acetate, 14520,B- (isoarnylthio) l 9-nor-A -pregnen-3 18-01 acetate, 146-20m-(2'-acetoxyethylthio) -19-nor-A -pregnene-3fi-ol acetate, 7 l47-20a- (2'-flu0r0ethylthi0) -19-nor-pregnen-3fi-0l acetate,

148-20u- (2'-chloroethylthio) -19-nor-A -pregnen- 35-01 acetate,

149-201 2-carboxyethylthio 19-nor-A -pregnen- 3 8-01 acetate,

15 20OL- 3 -hydroxy-3 '-metl1ylbutylthio) l9-n0r- A -pregnen-3B-ol acetate,

151-20m-(3'-n1ethyl-but-2-enylthio)-19-nor-A pregnen-3 5-01 acetate,

15 2200L- isoamylthio 1 9-nor-A -pre gnen-3 ,8-ol

acetate.

The compounds Nos. 33, 47, 62, 79, 94, 1 08 and 123 were treated by the above procedure, thus furnishing respectively:

Example XL The starting compounds of Example XXXIX were treated following exactly the procedure described in that example, except that acetic anhydride was substituted by caproic anhydride, propionic anhydride, enanthic anhydride and cyclopentylpropionic anhydride thus affording respectively the corresponding caproates, propionates, enanthates and cyclopentylpropionates of said starting compounds.

I claim:

1. A compound represented by the general formula:

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 7 carbon atoms, inclusive; R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms, and X is selected from the group consisting of hydrogen, halogen, an N,N-dialkyl amino group, a hydroxyl group, an acyl group containing less than 12 carbon atoms, a cyano group and a carboxyl group.

2. A compound represented by the general formula:

wherein R represents an aliphatic hydrocarbon residue containing from 1 to 7 carbon atoms, inclusive; R is selected from the group consisting of hydrogen and methyl, and X is selected from the group consisting of hydrogen, halogen, an N,N-dialkylamino group, a hydroxyl group, a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms, a cyano group and a carboxyl group.

3. -(2'-hydroxyethylthio)-A -pregnen-3,B-o1.

4. 20- (2-fiuoroethylthio) -A -pregnen-3,8-ol.

5. 20-(2'-chloroethylthio)-A -pregnen-3,B-ol.

6. 20-(2-carboxyethylthio)-A -pregnen-3,8-ol.

7. 20-[2'-(N,N-dimethylamino)-ethylthio] A pregnen-3/3-ol.

8. 20- 2'-hydroxyethylthio) -19-nor-A -pregnen-3B-ol.

10. 20- (2'-chloroethylthio -19-nor-A -pregnen-3fi-ol.

11. 20-(2-carboxyethylthio)-19-nor-A -pregnen-3fi-o1.

12. 20-[2-(N,N-di1nethylamino)-ethylthio] A pregnen-3fi-ol.

13 20- (2'-hydroxyethylthio) -A -pregnen-3-one.

14. 20-(2'-fluoroethylthio)-A -pregnen-3-one.

15. 20- 2-chloroethylthio -A -pregnen-3-one.

16. 20- 2'-carboxyethylthio) -A -pregnen-3-one.

17. 20-[2'-(N,N-dimethylamino)-ethylthio] A pregnen-B-one.

18. 20-(2-hydroxyethylthio) -19-nor-A -pregnen-3-one.

19. 20- (2'-fluoroethylthio) -19-nor-A -pregnen-3-one.

20. 20-(2-chloroethylthio)-19-nor-A -pregnen-3-one.

21. 20- (2'-carboxyethylthio) -19-nor-A -pregnen-3-one.

22. 20-[2-(N,N-dimethylamino)-ethylthio] 19 nor- A -pregnen-3-one.

References Cited in the file of this patent Barton et al.: .lourn Chem Soc. 1962 page 1967. 

2. A COMPOUND REPRESENTED BY THE GENERAL FORMULA: 